Lobaplatin induces pyroptosis through regulating cIAP1/2, Ripoptosome and ROS in nasopharyngeal carcinoma.

ABSTRACT

Cisplatin is the most commonly used chemotherapeutic drug for nasopharyngeal carcinoma (NPC), while its side effects are often intolerable. Lobaplatin, as an effective third-generation platinum with fewer adverse reactions and less platinum cross-resistance, has been considered as a good alternative to cisplatin after cisplatin's failure (relapse or metastasis) in the treatment of NPC. However, the anti-NPC mechanism of lobaplatin remains largely unknown. In present study, 50% inhibiting concentration (IC50) of lobaplatin for NPC cells is found to be similar to that of cisplatin. 10 µM and 20 µM lobaplatin caused obvious gasdermin-E (GSDME)-mediated pyroptosis by activating caspase-3. Moreover, we found lobaplatin induced proteasomal degradation of cell inhibitor of apoptosis protein-1/2 (cIAP1/2). And these pyroptotic phenomena could be suppressed by the recovery of cIAP1/2, suggesting that cIAP1/2 are critical in lobaplatin-induced pyroptosis. Further inhibition of cIAP1/2 by birinapant (an antagonist of cIAP1/2) dramatically enhanced pyroptosis induced by lobaplatin in vitro and in vivo, which was consistent with the combination with cisplatin. Importantly, this synergistic pyroptotic effect were suppressed by the inhibition of Ripoptosome (RIPK1/Caspase-8/FADD), reactive oxygen species (ROS) and caspase-3 cleavage, and were independent of phosphorylation of JNK and NF-κB signal. Our data reveal that cIAP1/2 play important roles in lobaplatin-induced NPC cell pyroptosis, and this anti-NPC effect can be significantly potentiated by cIAP1/2 antagonist birinapant through regulating the formation of Ripoptosome and the generation of ROS. These study provides a possibility to further reduce the platinum-related adverse events and chemoresistance of lobaplatin while maintaining satisfactory anti-NPC efficacy.